SINGLE-ORGANISM MODEL OF HOST-DEFENSE AGAINST INFECTION - A NOVEL IMMUNOTOXICOLOGIC APPROACH TO EVALUATE IMMUNOMODULATORY DRUGS

The immunotoxicologic effects of drugs on host defense have been studi ed widely using various animal models of infection. Here we describe a new approach to testing host defense by using a single organism (Cand ida albicans) in CBA/J mice. The model is configured to test 3 effecto r systems via different routes of inoculation to stimulate different e ffector arms of the immune response. Nonspecific immunity was evaluate d by C. albicans colony-forming unit (CFU) count from the spleen at 2 hr (uptake) and greater than or equal to 22 hr (clearance) following i ntravenous inoculation. Cell-mediated immunity was assessed by CFU cou nt from an intramuscular injection site 6 days postinoculation. Humora l immunity was assessed by anti-Candida antibody titer, following mult iple subcutaneous immunizations with C. albicans. Finally, overall imm unity was evaluated following intravenous injection using survival as the endpoint. Histopathological, immunohistochemical, and electron mic roscopic evaluation of selected tissues revealed the involvement of th e expected cell types in the different effector systems. Several immun omodulatory drugs-dexamethasone, cyclosporine, liposomal muramyltripep tide phosphatidylethanolamine, and SK&F 105685-were evaluated in the C . albicans model. Dexamethasone impaired host defense against C. albic ans by suppressing all endpoints measured. Similarly, cyclosporine sho wed broad immunosuppressive activity, with the exception of yeast upta ke from the spleen. In contrast, muramyl tripeptide-phosphatidylethano lamine enhanced all but cell-mediated immunity to C. albicans. SK&F 10 5685 displayed both stimulatory and inhibitory effects on immune respo nses to the infection. Our studies demonstrate that a single organism- based approach can be a useful method for evaluating the immunological hazards of drugs on host resistance to infection.